Photodynamic therapy (PDT) of various medical conditions usually involves i.v. administration of a photosensitizer, followed (after several hours up to a day) by the illumination of the affected tissue with red light. This results in activation of the sensitizer and subsequently the formation of reactive oxygen species (ROS), particularly singlet oxygen. Depending on the localization of the photosensitizer, the ensuing oxidative stress leads to vascular collapse and cell death involving apoptosis or necrosis (Oleinick et al., Photochem. Photobiol. Sci., 1: 1-22, 2002). Most photosensitizers currently in clinical use or in trials have one of the following drawbacks, or a combination thereof (Sharman et al., Drug Discovery Today, 4; 507-517, 1999): they consist of a mixture of products, they are lipophilic drugs, requiring formulation in liposomes or an emulsion, their photochemical properties are not optimal for PDT, their pharmacokinetics and target localization are not compatible with the selected application.
During the past decades phthalocyanines (Pc) and their derivatives have been extensively studied. Pc and their derivatives found numerous applications in widely different areas due to their distinct properties. Both lipid and water-soluble Pc have been advanced as photosensitizers for the photodynamic therapy (PDT) of cancer. Among the water-soluble derivatives particularly the efficacy of sulfonated metallo Pc has been studied. Depending on the degree of sulfonation, Pc exhibit varying hydrophobic and hydrophilic properties inducing different photodynamic effects. Adjacently substituted, disulfonated compounds have the appropriate amphiphilic properties for optimal cell membrane penetration, resulting in high photodynamic activity against tumor cells (Margaron et al., Photochemistry and photobiology, 63(2):217-223, 1996). Inherent to the classical procedure of their preparation, such derivatives are difficult to purify as single isomeric products and as such not suitable for human applications.
A particularly interesting application of PDT involves the treatment of wet age-related macular degeneration (AMD). Wet AMD is the leading cause of blindness for people over the age of 50 and involves the rapid growth of abnormal blood vessels under the central retina. Leakage from these abnormal vessels causes scarring and an accelerated loss of visual acuity. The retina is protected by a blood retinal barrier (BRB) constituted by two spatially distinct monolayers of cells, of which the tight junctions between retinal capillary endothelial cells forms the inner retinal barrier, and the retinal pigment epithelium forms the outer barrier. The BRB serves to keep the retina dry and preserves the ionic balance of the retina. In addition, some circulating factors may be toxic to the retina and are kept out by the BRB. Thus an intact BRB is essential for the normal function of the retina.
The BRB is breached in many retinopathies involving vascular disorders including macular degeneration, diabetic retinopathy, exudative retinal detachment, Coat's disease and various forms of macular edema. Plasma extravasation is a direct consequence of the BRB breakdown. Plasma extravasation results in the deposit of material, which is normally within the lumen of vessels onto the retina, resulting in the loss of vision at such sites due to obstruction of light transmission. Subretinal edema brought about by plasma extravasation will lead to detachment of essential cellular connections resulting in vision loss.
Evidence shows that Vascular Endothelial Growth Factor (VEGF), originally known as vascular permeability factor, is a key element in the breakdown of the BRB under pathological conditions (Quam, et al., Invest. Ophth. Visual Sci., 42: 2408-2413, 2001). Photodynamic therapy using a benzoporphyrin derivative (verteporfin) as a photosensitizer has been shown to be an efficient procedure to close the abnormal vessels, and has been accepted in several countries for the treatment of AMD (U.S. Pat. No. 5,756,541).
In a search for phthalocyanine-like structures that exhibit similar amphiphilic and cell penetrating properties as those of the disulfonated Pc, the synthesis and properties of trisulfonated Pc substituted with a lipophilic group on the fourth non-sulfonated benzyl group were previously investigated. In a first approach boron(III) subphthalocyanines were used as intermediates (U.S. Pat. No. 5,864,044). The success of this procedure depends dramatically on the nature of the substituents on the subPc, as well as other factors, and as such the procedure was found not to be suitable for the preparation of trisulfonated Pc with extended lipophilic substituents. Subsequently, it was found that such compounds could be obtained via palladium-catalyzed cross coupling reactions using a monoiodo trisulfonated Pc as starting material (Tian et al., Tetrahedron Lett., 41: 8435-8438, 2000). Such mono functionalized trisulfonated Pc exhibit the typical Q band near 680 nm.
It would be highly desirable to be provided with novel water-soluble amphiphilic photosensitizing drugs for the treatment of various medical conditions by photodynamic therapy (PDT) that overcome the drawbacks of the prior art compounds.
It would also be highly desirable to be provided with novel tri-(sulfobenzo)-mono-(carboxyl-naphtho)-porphyrazines compounds for attachment to a protein carrier such as an antibody, preferably a monoclonal antibody (Mab) or its fragments for the treatment of various medical conditions by PDT.